Molecular and biochemical pathologies in human alcohol-related cerebellar white matter degeneration

Background: Alcohol use disorder (AUD) marked by heavy chronic or binge alcohol consumption, causes cerebellar and white matter (WM) atrophy with cognitive-motor impairments. Major pathological features of alcohol-related brain damage (ARBD) include alterations in WM integrity with myelin loss, and cerebellar degeneration with neuronal loss. Purpose: This study characterizes molecular and biochemical oligodendrocyte-related pathology in cerebellar tissue from donors with AUD to better understand the mechanisms of ARBD in humans. Methods: Cores of cerebellar vermis, including cortex and underlying WM from adult human postmortem AUD and control brains, were processed for RNA and protein analyses using duplex and multiplex panels. Results: AUD cerebellar WM had significant alterations in immature and mature oligodendrocyte protein and mRNA expression, and reduced expression of hepatocyte growth factor, Akt and GSK-3β signaling molecules, and Notch pathway activation. Moreover, the only significant AUD-related alteration in cerebellar cytokine/chemokine expression was reduced IL-16 immunoreactivity. Conclusion: Human AUD WM degeneration is associated with oligodendrocyte dysfunction, which mechanistically could be mediated by impairments in insulin/IGF signaling through Akt/GSK-3β or Notch pathway activation. Future studies should focus on the non-invasive detection and monitoring of AUD-related oligodendrocyte pathology through the analysis of cell-type-specific exosomes isolated from peripheral blood.